inkjet printing of pharmaceuticals - homepage | ispe...and the use of raman spectroscopy for...

And the use of Raman spectroscopy for visualization and quality control

Magnus Edinger, PhD fellowDepartment of [email protected]

Inkjet printing of pharmaceuticals

mailto:[email protected]

Agenda

• About me

• Inkjet printing of pharmaceuticals

• Raman spectroscopy as Quality control

• Experiments

• Conclusions and further work

01/03/2017 2

About me…

• 2015: Cand.scient.pharm, Dep. Of Pharmacy, Uni. Copenhagen

• Subjects:

• Hot-melt extrusion & 3D printing

• Rheology of mixtures relevant in hot-melt extrusion

01/03/2017 3

About me…

• 2015: Cand.scient.pharm, Dep. Of Pharmacy, Uni. Copenhagen

• 2015-2018 Ph.d. student, Section of pharmaceutical technology and Engineering, Dep. Of Pharmacy, Uni Copenhagen

01/03/2017 4

“Flexible manufacturing of Inkjet-printed Dosage Forms”

Jukka Rantanen, ProfessorNatalja Genina, Assist. Prof. Daniel Bar-Shalom, Assoc. Prof.

Visualization and Non-Destructive Quantification of Inkjet-

Printed Pharmaceuticals on Different Substrates Using Raman

Spectroscopy and Raman Chemical Imaging

Magnus Edinger, Daniel Bar-Shalom, Jukka Rantanen, Natalja Genina

Pharmaceutical Research, 2017 (in press)


01/03/2017 5

• One size fits all principle

Personalized/Precision Medicine


01/03/2017 6

Dose flexibility

Combination doses

Manufacture on demand

”High throughput”

Control of properties of final dosage form

(faster dissolution, controlled delivery)

Personalized medicine

Low-dose APIs

Low output

Quality control of inkjet-printed pharmaceuticalsAPI Content:

UV spectroscopy/HPLC (destructive)

Non-destructive:

Near-infrared spectroscopy

Raman spectroscopy

Raman chemical imaging

01/03/2017 7

Equipment

01/03/2017 8

• PixDro LP50 (Meyer Burger Technologies)*

* Åbo Akademi, Niklas Sandler

Inkjet Printing

01/03/2017 9

• Ink base: non-toxic and not too volatile.

• Examples: Ethanol, water,

• Polyethylene glycols,

• Polypropylene glycols

• API soluble in ink base

• Substrates

• Any form – tablet, film, foam, etc

• Any pharmaceutically approved excipient

Kolakovic et al. Exp. Opin. On Drug Del. 2013 10(12)

Inkjet Printing

API Content• Concentration 160 mg/mL

• Droplet size 62 pl

• Dots per inch (DPI) 450 (max)

• Area -

• Layers -

= 0.31 mg API/layer/cm2

01/03/2017 10

Kolakovic et al. Exp. Opin. On Drug Del. 2013 10(12)

Raman spectroscopy

01/03/2017 11

Tong Zhang presentation, Renishaw UK PLC

Raman spectroscopy

Inelastic scattering• Relies on shift in photon

wavelength after absorbance in molecular bonds

01/03/2017 12

Tong Zhang presentation, Renishaw UK PLCWikipedia, Raman spectroscopy

Raman spectroscopy vs. IR spectroscopy

• Haloperidol

01/03/2017 13

Infrared

Raman

• IR: measures change in dipole moment of molecular bonds.

• Raman: Measures polarizability of molecular bonds


• Extension to Raman spectroscopy

01/03/2017 14

Laser

JM Amigo, Anal Bioanal Chem, 2010 (398)

l

X * Y


01/03/2017 15

Laser

JM Amigo, Anal Bioanal Chem, 2010 (398)

Data preprocessing

Principal component analysis(PCA)


Principal component analysis

• Method for visualizing patterns in datasets

• Decomposes data into sources of greatest variation

• Scores plot

• Loadings plot

• %

01/03/2017 16

Loadings PT (F × l)

94.5 % 3.4 % 1.9 %

Data preprocessing

01/03/2017 17

Raw sample data

Masking

Done in order to remove

BackgroundNoiseScatteringEtc.

Data preprocessing

01/03/2017 18

Raw spectral data (1008 spectra)

Standard Normal VariateTransformation

Savitzky-Golay

smoothing

81 point window,

2nd order polynomial,

2nd derivative

Data preprocessing

01/03/2017 19

Why do preprocessing?

• Removing noise • Removing baseline variation• Enhancing subtle differences between spectra:

Materials and Methods

01/03/2017 20

• API: Haloperidol

• Antipsychotic

• (Schizophrenia and psychosis treatment)

• 0.5 – 5 mg dose

• Adverse effects common

• Low aqueous solubility

• Highly soluble in lacticacid


01/03/2017 21

• Ink base:

• Haloperidol

• Lactic acid 14%

• Ethanol 86%

• Erythrosine for coloring

• Final concentration of Haloperidol: 160 mg/mL


01/03/2017 22

• API: Haloperidol

• Substrates:

• Calcium hydrogen phosphate (CaHPD) compacts

• Commonly used tablet filler

• Weak Raman scatterer

• Uncoated commercial paracetamol tablets (500 mg)

• Go-to OTC analgesic

• Strong Raman scatterer

1 cm


• Printing on substrates

01/03/2017 23

6mm

15mm

8 mm

5 and 10 layers1.4 – 2.8 mg

1 2 5 10 layers0.16 0.3 0.8 1.6 mg


• CaHPD tablets

• 1, 2, 5 and 10 layers

01/03/2017 24

8 mm

10 mm

41 data points

(250mm/point)

10 mm

41 data points

(250mm/point)


01/03/2017 25

10 mm

41 data points

(250mm/point)

10 mm

41 data points

(250mm/point)9 seconds/point

1681 points

4.2 hours/analysis

• CaHPD tablets

• 1, 2, 5 and 10 layers

Raman chemical imaging• Paracetamol tablets

• 5 and 10 layers

01/03/2017 26

0.28 mg/layer

Raman mapping

19 mm

48 points

(400mm/point)

8 mm

21 points

(400mm/point)


01/03/2017 27

Raman mapping

19 mm

48 points

(400mm/point)

8 mm

21 points

(400mm/point)

10 seconds/point

1008 points

2.8 hours/analysis

• Paracetamol tablets

• 5 and 10 layers

Results – Raman chemical imagingCaHPD tablets

01/03/2017 28

Pure tablet 1 Layer 2 layers

5 layers 10 layers 10 layers

Principal component 1

99.8 %

Edinger, M. et al, Pharm Res. 2017, (in press)

Results – Raman mappingCaHPD tablets

01/03/2017 29


CaHPD


99.8 %



01/03/2017 30


Pure tablet 1 Layer 2 layers

5 layers 10 layers 10 layers

0.17 %



01/03/2017 31


Haloperidol ink


0.17 %


01/03/2017 32

Tablets 5 layers 10 layers

Results – Raman chemical imagingPrincipal component 1


01/03/2017 33

• Paracetamol tablet

Results – Raman chemical imagingPrincipal component 1


Results – Raman chemical imaging

01/03/2017 34

• Principal component 2

Tablets 5 layers 10 layers



Results – Raman mapping

01/03/2017 35

PBP World Meeting 2016


Haloperidol ink



Results – Raman mapping

• Possible to visualize API on inkjet printed samples.

• LONG analysis time

• Is it possible to shorten analysis time and get quantitative data?

01/03/2017 36

Quantification of haloperidol using Raman spectroscopy?

01/03/2017 37

Quantification of haloperidol using Raman spectroscopy?

• CaHPD compacts

01/03/2017 38

10 mm 8 mm 6 mm

Tablet Printed area Area of analysis

6mm

15mm3 mm

• Paracetamol tablets

Preprocessing

01/03/2017 39

0 layers1 layer2 layers5 layers 10 layers

Preprocessing

Spectral

selection

CaHPM compactsRaw spectra

PLS modeling – CaHPM compacts

• Correlating to HPLC data

01/03/2017 40

mg haloperidol (measured)

mg

halo

peri

do

l (p

red

icte

d) R2 = 0.99

RMSEP = 80 mg

Preprocessing

01/03/2017 41

0 layers5 layers 10 layers

Preprocessing

Spectral

selection

CaHPM compactsRaw spectra

PLS modeling – Paracetamol tablets

• Correlating to HPLC data

01/03/2017 42

mg haloperidol (measured)

mg

halo

peri

do

l (p

red

icte

d) R2 = 0.90

RMSEP = 0.2 mg

Conclusions

• It is possible to use Raman chemical imaging to visualize inkjet printed pharmaceuticals even on strongly Raman scattering substrates

• It is possible to non-destructively quantify inkjet printed pharmaceuticals using Raman spectroscopy and PLS modeling. • Lower accuracy on strong Raman scatterers

• Penetration depth of ink and Raman laser

01/03/2017 43

Future work

• Implementation of transmission Raman spectroscopy methods for API quantification

• Development of substrates optimized for inkjet printing of pharmaceuticals

• Printing APIs as their own quality control – QR codes

01/03/2017 44

Thanks to…

Jukka Rantanen, Professor

Natalja Genina, Assist. Prof.

Daniel Bar-Shalom, Assoc. Prof

Henrik Launio, MSc student

Laura-Diana Iftimi, MSc student

Section of Pharmaceutical Technology and Engineering

01/03/2017 45

Niklas Sandler, Prof.

Henrika Wickström, PhD fellow

Mirja Palo, PhD fellow

Anders V. Friderichsen

Jian X. Wu

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